Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 93, Issue 3, Pages 452-462Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2013.07.011
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Funding
- National Institutes of Health [1P01HL098053, 5P01HD32573]
- [NSF-CCF-1115206]
- [NSF-III-1318386]
- [5RO1-HG004962]
- [U54 HL108460]
- Direct For Computer & Info Scie & Enginr
- Division of Computing and Communication Foundations [1115206] Funding Source: National Science Foundation
- Direct For Computer & Info Scie & Enginr
- Div Of Information & Intelligent Systems [1318386] Funding Source: National Science Foundation
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The hypoxic conditions at high altitudes present a challenge for survival, causing pressure for adaptation. Interestingly, many high-altitude denizens (particularly in the Andes) are maladapted, with a condition known as chronic mountain sickness (CMS) or Monge disease. To decode the genetic basis of this disease, we sequenced and compared the whole genomes of 20 Andean subjects (10 with CMS and 10 without). We discovered 11 regions genome-wide with significant differences in haplotype frequencies consistent with selective sweeps. In these regions, two genes (an erythropoiesis regulator, SENP1, and an oncogene, ANP32D) had a higher transcriptional response to hypoxia in individuals with CMS relative to those without. We further found that downregulating the orthologs of these genes in flies dramatically enhanced survival rates under hypoxia, demonstrating that suppression of SENP1 and ANP32D plays an essential role in hypoxia tolerance. Our study provides an unbiased framework to identify and validate the genetic basis of adaptation to high altitudes and identifies potentially targetable mechanisms for CMS treatment.
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